Discovery of the widespread and impressive properties of fluoroimidazoles as biological substrates and analogs has provided the impetus for the synthesis of other substituted imidazoles. Novel methods have been developed for the synthesis of previously unknown or difficultly accessible 2-substituted imidazoles. Thus, all 2-halohistamines and 2-halohistidines are now available as well as analogs containing the amino, formyl, cyano, and nitro and azido groups. As predicted by electronic considerations, 4-trifluoromethylimidazoles generate fulvene intermediates much more readily than do their 2-isomers. The former compounds are expected to prove useful as receptor affinity lables for use in vivo. 2-Nitroimidazoles undergo reduction with mercaptans to generate imidazolyl radicals, which may be potent alkylating agents. Thus, a mechanism may have been found for the selective cytotoxic effect of these compounds on cancer cells. The very high methyl acidity of 1,5-dimethyl-4-nitroimidazole provides further evidence for the low aromaticity of imidazoles.